Activated PIK3CD drives innate B cell expansion yet limits B cell-intrinsic immune responses

J Exp Med. 2018 Oct 1;215(10):2485-2496. doi: 10.1084/jem.20180617. Epub 2018 Sep 7.


Activated PI3K-delta syndrome (APDS) is an immunodeficiency caused by gain-of-function mutations in PIK3CD. This disease exhibits complex immune phenotypes including increased IgM, recurrent infection, and impaired vaccine responses. To better understand the impact of B cells in this disease, we generated an inducible model of the common APDS mutation (hPIK3CD-E1021K; referred to as aPIK3CD) and intercrossed these mice with B cell-specific Cre models. Mb1-aPIK3CD mice exhibited bone marrow B lymphopenia and, conversely, expansion of the peripheral innate B1a and MZ B cell compartments. aPIK3CD B cells manifest increased pS6 and increased survival at several stages, without alterations in cycling, and baseline increases in plasma cells, natural IgM, and IgG3. Finally, Mb1-aPIK3CD mice exhibited blunted T cell-independent immune responses, and both AID- and CD21-aPIK3CD mice displayed reduced class-switched antibodies following T cell-dependent immunization. Thus, aPIK3CD alters B cell development and function and is counter-productive during immune responses, providing insight into B cell-intrinsic contributions to the APDS phenotype.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Class I Phosphatidylinositol 3-Kinases / genetics
  • Class I Phosphatidylinositol 3-Kinases / immunology
  • Enzyme Activation / genetics
  • Enzyme Activation / immunology
  • Gain of Function Mutation*
  • Genetic Diseases, Inborn / genetics
  • Genetic Diseases, Inborn / immunology*
  • Genetic Diseases, Inborn / pathology
  • Immunity, Innate*
  • Immunologic Deficiency Syndromes / genetics
  • Immunologic Deficiency Syndromes / immunology*
  • Immunologic Deficiency Syndromes / pathology
  • Mice
  • Mice, Knockout
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / immunology*
  • Plasma Cells / immunology*
  • Plasma Cells / pathology
  • Primary Immunodeficiency Diseases


  • Class I Phosphatidylinositol 3-Kinases
  • Pik3cd protein, mouse

Supplementary concepts

  • Activated PI3K-delta Syndrome